1. Academic Validation
  2. Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids

Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids

  • J Exp Clin Cancer Res. 2020 Jan 28;39(1):22. doi: 10.1186/s13046-020-1523-2.
Siqi Wang 1 2 Yang Wang 1 2 Xiaodong Xun 1 Changkun Zhang 1 Xiao Xiang 1 Qian Cheng 1 3 Shihua Hu 1 Zhao Li 4 5 6 7 Jiye Zhu 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China.
  • 2 Beijing Key Laboratory of HCC and Liver Cirrhosis, Beijing, China.
  • 3 Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China.
  • 4 Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China. goodlizhao@sina.com.
  • 5 Beijing Key Laboratory of HCC and Liver Cirrhosis, Beijing, China. goodlizhao@sina.com.
  • 6 Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China. goodlizhao@sina.com.
  • 7 Peking University Institute of Organ Transplantation, Beijing, China. goodlizhao@sina.com.
  • 8 Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China. liver@bjmu.edu.cn.
  • 9 Beijing Key Laboratory of HCC and Liver Cirrhosis, Beijing, China. liver@bjmu.edu.cn.
  • 10 Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China. liver@bjmu.edu.cn.
  • 11 Peking University Institute of Organ Transplantation, Beijing, China. liver@bjmu.edu.cn.
Abstract

Background: The mechanism underlying sorafenib resistance in hepatocellular carcinoma (HCC) remains unclear. Accumulating evidence suggests that tumor-initiating cells (TICs) are a pivotal driving force. Both CD44 and Hedgehog signaling play crucial roles in TIC properties in HCC. In this study, we explored the roles of CD44 and Hedgehog signaling in sorafenib resistance and evaluated the therapeutic effect of cotreatment with sorafenib and Hedgehog signaling inhibitors in HCC patient-derived Organoid (PDO) models to improve treatment efficacy.

Methods: We collected HCC specimens to establish PDO models. Cell viability and malignant transformation properties were investigated after treatment with different TIC-related inhibitors alone or in combination with sorafenib to evaluate the therapeutic effect in PDOs and cell lines by in vitro and in vivo experiments. Expression levels of Hedgehog signaling proteins and CD44 were monitored to reveal potential relationships.

Results: We demonstrated that our HCC PDO models strongly maintained the histological features of the corresponding tumors and responded to drug treatment. Furthermore, CD44-positive HCC PDOs were obviously resistant to sorafenib, and sorafenib increased CD44 levels. A drug screen showed that compared with Notch, Hippo and Wnt signaling inhibitors, a Hedgehog signaling inhibitor (GANT61) potently suppressed HCC PDO cell viability. In addition, there was a highly synergistic effect in vitro and in vivo on the suppression of cell viability and malignant properties when sorafenib and GANT61 were added to CD44-positive HCC PDOs and cell lines, respectively. Furthermore, the upregulation of CD44 and Hedgehog signaling induced by sorafenib was reversed by GANT61.

Conclusions: GANT61 significantly suppressed Hedgehog signaling to reverse sorafenib resistance in CD44-positive HCC. The combination of sorafenib and Hedgehog signaling inhibitors might be effective in HCC patients with high CD44 levels as a personalized-medicine approach.

Keywords

CD44; Hedgehog signaling; Hepatocellular carcinoma; Patient-derived organoids (PDOs).

Figures
Products